Stroke – Stem Cells Can Reduce Brain Damage

Rescuing a patient from a stroke and restoring cognitive functions are two significant medical challenges today. Blockage of a brain artery, usually by a clot or atherosclerotic plaque, results in reduction in oxygen supply to brain cells. If the supply of oxygen is interrupted for a long time, brain cells die resulting in severe loss of motor and cognitive functions. Therapeutic approaches to prevent the formation of plaques or blood clots are not a hundred percent successful in preventing a stroke. Recent research has focused on aiding regeneration of brain cells after an ischemic stroke and stem cells have been used with reasonable success.

Experiments conducted on rats show that intravenous injection of stem cells derived from adipose tissues as well as mesenchymal stem cells derived from bone marrow supported the recovery of brain cells after a stroke. In these experiments, rats were subjected to a stroke by blocking their middle cerebral artery permanently. Stem cells from bone marrow as well as fat cells were injected 30 minutes after induction and the health of the animals was assessed at 24 hours and 14 days after stroke. In the recovery period, animals injected with stem cells showed increased levels of vascular endothelial growth factor and synaptophysin. The injected stem cells did not migrate to the site of the lesion but presumably acted as a source of neurotrophic growth factors.

In another study, stem cells from the dental pulp of human deciduous teeth (milk teeth) were grafted in the brains of mice one day after induction of a stroke. In some animals, the culture medium in which these cells were grown was used instead of the cells. Mice treated with human dental pulp stem cells and conditioned medium from these cells showed better recovery and neurological outcome than untreated mice. Grafted stem cells as well as the conditioned medium inhibited death of neurons in the recovery period and prevented cell destruction resulting from inflammation. In these experiments, the actual integration of human dental pulp stem cells into the brain tissue occurred at very low frequency.

Both studies present important insights in the process of regeneration of brain cells followed hypoxic and ischemic stroke. Stem cells secrete a number of growth factors which help to promote generation of new neurons post a stroke. The results presented by Yamagata and colleagues where just the culture medium from dental pulp stem cells was effective in restoring brain tissue and neurological functions indicate that a suitable “growth factor cocktail” can be derived from cultures of stem cells to treat stroke. Since intravenous injection of stem cells also helps recovery from stroke, it is easy to deliver such a therapeutic intervention. A xenograft of human dental pulp stem cells was successful in helping mice recover from a stroke. It would be interesting to know whether stem cells from other animal systems have a similar beneficial effect on human neurons as well.

I was recently contacted by a patient with chemo resistant metastatic esophageal cancer. This is the 2nd patient in a row with this condition. The prior one presented with stage 4 esophageal cancer. We had to determine if the cancer is/is not in the bone marrow to assess how much it has metastasized or whether it is localized to the esophagus. In any case, the first patient was treated with the protocol I posted previously and it reduced the cancer cell markers by 40% within 3 weeks. The mesenchymal stem cells recruited NTK (Natural Killer Cells) which reduce the tumors and cancer cell markers. The patient is now 3 months post op (as of 1/26/13) and is doing extremely well. He is at Stage 1 down from Stage 4. He has decided to receive a second treatment and we are hopeful he will retain full remission.
– DG

Stem cells for cancer? Yes.

This works because:
“…tumor-oriented homing capacity of mesenchymal stem cells (MSCs), the application of specific anticancer gene-engineered MSCs has held great potential for cancer therapies. The dual-targeted strategy is based on MSCs’ capacity of tumor-directed migration and incorporation and in situ expression of tumor-specific anticancer genes.”
From http://www.wjgnet.com/1948-0210/pdf/v3/i11/96.pdf

“Adult stem cells are derived from blood, umbilical cords, bone marrow, placenta, fat tissue, muscle, nasal neurological, breast milk, menstruation, dental pulp, lungs, eyes, pancreas and many more locations. While some are better than others for regenerative treatment, it has long been believed that those cells derived from reproductive associated organs are some of the most powerful. This study shows that umbilical cord derived stem cells are not as great as once believed.”
“In fact, compared to the 100% of mesenchymal stem cells found in cells derived from adipose (fat), only 67% of cord blood stem cells are mesenchymal and lend themselves toward regenerative treatments.* While bone marrow derived stem cells also have 100% mesenchymal cells, they have reduced proliferation and have a history of causing malignant cells – ‘In addition, Izadpanah et al.** demonstrated that long-term cultivation of MSC beyond passage 20 may result in their transformation to malignant cells.”***

Only A Specific Group Of Cord Blood Stem Cells Found To Be Efficient For Use In Regenerative Medicine

Scientists at the University of Granada and Alcala de Henares University have found that not all isolated stem cells are equally valid in regenerative medicine and tissue engineering. In a paper recently published in the prestigious journal Tissue Engineering the researchers report that, contrary to what was thought, only a specific group of cord blood stem cells (CB-SC) maintained in culture are useful for therapeutic purposes.

At present, CB-SCs are key to regenerative medicine and tissue engineering. From all types of CB-SC those called “Wharton’s jelly stem cells (HWJSC)” are stirring up the interest of specialists in regenerative medicine, due to their accessibility and great ability to develop into several types of tissue and modulate immune responses.

Through a combination of microscopy and microanalysis essays, and the study of the genes involved in cell viability, the researchers discovered that only a specific group of cord blood stem cells (CB-SC) maintained in culture is useful for therapeutic purposes

The Most Suitable Cells

The relevance of this paper, which was the cover article in the journal Tissue Engineering, lies in the possibility to select the most suitable HWJSC for tissue engineering and regenerative medicine. According to these researchers, the different studies with HWJSC have obtained contradictory results because researchers failed to previously select the most suitable cell group.

The results of this study also open the possibility to select stem cell subgroups from different tissues, in order to improve the therapeutical efficacy of different regenerative medicine protocols.

This research study was conducted by the Tissue Engineering research group at the University of Granada Histology Department coordinated by professor Antonio Campos Muñoz, who recently created artificial skin and a cornea by using stem cells and new biomaterials developed in Granada.

The research group is also composed of professors Alaminos Mingorance and Ingrid Garzón. Professor Garzon was awarded a prize at the World Congress on Tissue Engineering and Regenerative Medicine held in Seul for a preliminary study on the same issue.

Dental pulp stem cells: a promising tool for bone regeneration.

Human tissues are different in term of regenerative properties. Stem cells are a promising tool for tissue regeneration, thanks to their particular characteristics of proliferation, differentiation and plasticity. Several “loci” or “niches” within the adult human body are colonized by a significant number of stem cells. However, access to these potential collection sites often is a limiting point. The interaction with biomaterials is a further point that needs to be considered for the therapeutic use of stem cells. Dental pulp stem cells (DPSCs) have been demonstrated to answer all of these issues: access to the collection site of these cells is easy and produces very low morbidity; extraction of stem cells from pulp tissue is highly efficiency; they have an extensive differentiation ability; and the demonstrated interactivity with biomaterials makes them ideal for tissue reconstruction. SBP-DPSCs are a multipotent stem cell subpopulation of DPSCs which are able to differentiate into osteoblasts, synthesizing 3D woven bone tissue chips in vitro and that are capable to synergically differentiate into osteoblasts and endotheliocytes. Several studies have been performed on DPSCs and they mainly found that these cells are multipotent stromal cells that can be safety cryopreserved, used with several scaffolds, that can extensively proliferate, have a long lifespan and build in vivo an adult bone with Havers channels and an appropriate vascularization.

Dental stem cell banking facility launched by Stemade Biotech this week in Punjab, India with the intent to expand across the county. “This will help the people to secure their healthy future. Like timely monetary investments help plan future financial security, dental stem cell banking can help plan for a disease- free body.” said Dr Vikas Jindal.

“Stem cells have a defining property to self- regenerate, which can be used to treat serious ailments. Unlike bone marrow stem cells, extracting dental cells is a noninvasive procedure. Dental pulp contains stem cells, known as dental pulp stem cells. The finest dental pulp stem cells are found in baby teeth or milk teeth. Dental stem cells can generate solid structures such as bone, new dental tissue, cartilage and muscle. Dental pulp stem cell banking can be done on milk teeth of children in the age group of five to 12. Teens that are undergoing orthodontic procedures, such as getting braces, have the opportunity to bank their premolars that are often extracted during the procedure. Adults on the other hand have the opportunity to bank on their dental pulp stem cells through wisdom teeth.”

We know stem cells work on MS, we just hadn’t figured out exactly how yet…and now we have!

– DG

CLEVELAND, Ohio — One of the most promising and exciting treatment avenues for multiple sclerosis is the use of a patient’s own stem cells to try to stop — or even repair — some of the disease’s brain tissue damage.

But injecting a patient with a dose of his or her own bone-marrow stem cells was actually a pretty crude method of treating the disease, because no one was quite sure how or why it worked. Last year, doctors at the Cleveland Clinic, University Hospitals Seidman Cancer Center and Case Western Reserve University began trying this for MS patients in a Phase 1 clinical trial after positive results were seen in mice.

Multiple sclerosis is an autoimmune disease in which the immune system attacks the myelin sheaths that surround and protect nerve cells. When myelin is damaged, the nerve cells are exposed and unable to do their job, which is sending signals to the brain and back. This results in the loss of motor skills, coordination and cognitive abilities.

Like many other researchers using stem cells, the local group didn’t know exactly how their treatment worked, but they knew that when they gave these human mesenchymal stem cells, or MSCs, to mice with a mouse version of the disease, the mice got better.

Figuring out why the mice improved could help researchers see if the MSC injection will work well in a particular patient before the patient is injected, and possibly augment or improve the treatment as well.

In May, the research group at CWRU, headed up by neurosciences professor Robert Miller, discovered exactly what it is in the stem-cell soup that has a healing effect: a large molecule called hepatocyte growth factor, or HGF. The team published their results in Nature Neuroscience.

Miller’s group knew that it could be the stem cells themselves, by coming in physical contact with the myelin damage, that were having a healing effect. Or it could be something the stem cells secreted into the surrounding liquid culture, or media, they were grown in, that was key. HGF is secreted by the stem cells, Miller said.

The team identified the HGF by first injecting only the liquid the stem cells were grown in, but not the stem cells themselves, into the mice they were studying. The mice got better, so the team knew whatever was helping was in the media.

Next, they isolated the small, medium and large molecules from the media and tried each size on the mice. Only the large-molecule treatment had the healing effect, meaning that whatever was helping was somewhere in that mix, Miller said.

“The molecule that jumped out at us was HGF,” he said, because it is the right size, is made by MSCs, and in a couple of studies had been shown to be involved in myelin repair.

So the scientists took a purified sample of HGF and injected it into the sick mice. They got better. When they blocked the receptor for HGF in the mice, they stayed sick. It was pretty compelling evidence that they’d found what they’d been looking for, Miller said.

“We went on to show that HGF, like the MSCs, is regulating both the immune response, and it is independently promoting myelin repair in the brain,” he said.

MSCs, taken from the bone marrow, are currently being tested in more than 150 clinical trials in the United States and around the world to treat conditions such as osteoarthritis, diabetes, emphysema and stroke.

The local Phase 1 trial has enrolled 16 of 24 total patients, and eight of them have completed the trial protocol, said Dr. Jeffrey Cohen, Cleveland Clinic neurologist and lead investigator of the trial.

So far, the treatment seems to be working, Cohen said.

“It’s a little early to be saying it, but things have looked encouraging.”

And there have been no safety concerns and almost no side effects. There has also been no activation — an aggravation or return of symptoms — of this relapsing disease in the patients involved, which has happened unexpectedly with other types of MS treatments.

Miller’s discovery won’t change the course of the trial currently under way at the Clinic and UH, but it may change the future of MSC treatment.

While they don’t know yet what the outcome of that trial will be, it’s possible that if a patient doesn’t respond to the treatment, it could mean that his stem cells aren’t producing enough HGF to be effective at healing, Miller said. Miller will be studying MSC samples from all the patients in the trial to find out if those who are better at producing HGF fare better.

He’ll also be trying to see if they can predict how well a patient will do based on his HGF levels in the MSC sample.

“Finally, though we’re a long way from this, maybe we could augment the expression of HGF in patients whose stem cells aren’t that effective to enhance their effectiveness,” he said.

But why not just inject the HGF alone? Miller said there are two reasons. First, the receptor for HGF in the cells, called c-MET, has been implicated in liver and breast cancer. Injecting HGF by itself into the body may stimulate the c-MET pathway, he said, and the research team is not willing to risk that.

“The stem cells have the advantage that they tend to home to the area of insult, so they don’t stick around in other parts of the body,” he said. “They target the treatment where it’s needed.”

Miller said his group is experimenting with a way of delivering HGF directly into the area of injury in the brain to minimize its contact with the rest of the body. HGF and c-MET are not associated with brain tumors.

They are also trying to test small fragments of the growth factor as a treatment, to see if they can eliminate some of the cancer concerns.

Cohen’s group hopes to have results from the Phase 1 trial available in the spring and has already started planning a larger study based on those results.